Calcineurin Signaling Mediates Activity-Dependent Relocation of the Axon Initial Segment
| Autor: | Rosanna P. Sammons, Matthew S. Grubb, Sabrina Lebron, Mark D. Evans, John J. Renger, Thomas B.K. Watkins, Victor N. Uebele, Adna S. Dumitrescu |
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| Rok vydání: | 2013 |
| Předmět: |
Dendritic spine
Dendritic Spines Population Action Potentials Biology Transfection Hippocampus Article Channelrhodopsins Piperidines Cyclosporin a medicine Animals Rats Wistar Axon education Cells Cultured Homeodomain Proteins Neurons education.field_of_study NFATC Transcription Factors Calcineurin Tumor Suppressor Proteins General Neuroscience Depolarization Calcium Channel Blockers Embryo Mammalian Axon initial segment Axons Rats Luminescent Proteins medicine.anatomical_structure Benzamides Calcium Calcium-Calmodulin-Dependent Protein Kinase Type 2 Excitatory Amino Acid Antagonists Neuroscience Photic Stimulation Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 33:6950-6963 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | The axon initial segment (AIS) is a specialized neuronal subcompartment located at the beginning of the axon that is crucially involved in both the generation of action potentials and the regulation of neuronal polarity. We recently showed that prolonged neuronal depolarization produces a distal shift of the entire AIS structure away from the cell body, a change associated with a decrease in neuronal excitability. Here, we used dissociated rat hippocampal cultures, with a major focus on the dentate granule cell (DGC) population, to explore the signaling pathways underlying activity-dependent relocation of the AIS. First, a pharmacological screen of voltage-gated calcium channels (VGCCs) showed that AIS relocation is triggered by activation of L-type Cav1 VGCCs with negligible contribution from any other VGCC subtypes. Additional pharmacological analysis revealed that downstream signaling events are mediated by the calcium-sensitive phosphatase calcineurin; inhibition of calcineurin with either FK506 or cyclosporin A totally abolished both depolarization- and optogenetically-induced activity-dependent AIS relocation. Furthermore, calcineurin activation is sufficient for AIS plasticity, because expression of a constitutively active form of the phosphatase resulted in relocation of the AIS of DGCs without a depolarizing stimulus. Finally, we assessed the role of calcineurin in other forms of depolarization-induced plasticity. Neither membrane resistance changes nor spine density changes were affected by FK506 treatment, suggesting that calcineurin acts via a separate pathway to modulate AIS plasticity. Together, these results emphasize calcineurin as a vital player in the regulation of intrinsic plasticity as governed by the AIS. |
| Databáze: | OpenAIRE |
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